The objective of this course is to give students the most up-to-date information on the biological, personal, and societal relevance of sleep. Personal relevance is emphasized by the fact that the single best predictor of daytime performance is the quality of the previous night's sleep. The brain actively generates sleep, and the first section of the course is an overview of the neurobiological basis of sleep control. The course provides cellular-level understanding of how sleep deprivation, jet lag, and substances such as alcohol, ,caffeine, and nicotine alter sleep and wakefulness. The second section of the course covers sleep-dependent changes in physiology and sleep disorders medicine. Particular emphasis will be placed on disorders of excessive sleepiness, insomnia, and sleep-dependent changes in autonomic control. Chronic sleep deprivation impairs immune function and may promote obesity. Deaths due to all causes are most frequent between 4:00 and 6:00 a.m., and this second section of the class highlights the relevance of sleep for preventive medicine. The societal relevance of sleep will be considered in the final section of the class. In an increasingly complex and technologically oriented society, operator-error by one individual can have a disastrous negative impact on public health and safety. Fatigue-related performance decrements are known to have contributed as causal factors to nuclear power plant failures, transportation disasters, and medical errors.

Helen Baghdoyan, Ph.D.

Transcript

One of the common concerns with benzodiazepine receptor medications is that they may be abused by patients. This particular study actually evaluated whether or not that was true. It looked at the abuse liability of a variety of different hypnotic agents shown in the graph among individuals who had a history of substance use disorders. In this case, abuse liability was defined as a ratings of the likelihood of abuse as well as the consequences of abuse or toxicity. In this particular study and randomized controlled format, individuals with a history of substance use disorders were administered these different hypnotic agents and placebo and then asked to make ratings. It's important to note that all benzodiazepine receptor agonists are class IV controlled substances. And you can see by the box that those benzodiazepine receptor agonists were rated as being of moderate to high abuse liability among this group of substance use disorder patients. By contrast, the melatonin receptor agonists which are nonscheduled medications, and here we're talking about Rozerem or ramelteon, had virtually no abuse liability. It's important to note that among individuals who have insomnia and no substance use history, there's no evidence that these medications are likely to be abused by those individuals as a group. However, among those individuals who have a history of substance use, benzodiazepine receptor agonist medications should likely be avoided for sleep. However, it may be reasonable in this population to try melatonin receptor agonist medications. Let's look at those for a second. Rozerem is the main melatonin receptor agonist that's been developed and is approved by the FDA for insomnia. It's a potent selective MT1/MT2 receptor agonist which has minimal affinity for the MT3 binding sites. It also is important to note that it has negligible affinity for GABA A receptor complex, the one that's typically targeted by the benzodiazepine receptor agonist. It also has negligible affinity for other systems such as dopaminergic systems, serotonin, ACh, glutamate, noradrenaline, or opiate receptors. And Rozerem has a half life that's relatively short from 1-2.6 hours but it does have an active metabolite that has a half life of 2-5 hours. So how does Rozerem work? There've been a few studies. This is probably the largest study that's evaluate the efficacy or the effects of Rozerem as a hypnotic agent. It was conducted in about 400 adults who had primary insomnia. Again, that's insomnia that typically doesn't have co-occurring medical or psychiatric conditions. And this group received placebo or two different doses of ramelteon, eight milligrams or 16 milligrams, for five consecutive weeks. The outcome in the graph is latency to persistent sleep or ability to fall asleep and stay asleep by polysomnography, measured objectively by polysomnography. And you can see that at baseline, there was no significant difference between the three groups. But by week one, the two doses of ramelteon helped people fall asleep and stay asleep faster than the placebo group, and these effects were sustained at five weeks. So it seems that Rozerem can help individuals fall and stay asleep quickly. It should be noted, however, that in this study, there were no differences between placebo and either dose of ramelteon at week five for total sleep time, sleep efficiency, or time awake during the night. Other metrics, we consider to be important when evaluating sleep and effects of hypnotics. So in summary, this study suggests Rozerem may be useful for individuals who have trouble only falling asleep. But if individuals have trouble falling and staying asleep, Rozerem is not likely to be a good choice of agent. Finally, let's look at the newest FDA approved medication which is Doxepin, low dose Doxepin. Doxepin is an older antidepressant that works at a number of different systems but it's thought that in these low doses, it's mostly has sedative effects that are related to histaminergic antagonism. In this particular study, they looked at the effects of Doxepin versus placebo in about 250 elderly subjects who, again, had primary insomnia. In this study, they received their placebo or again two doses of Doxepin, one or three milligrams for 12 weeks in a randomized controlled trial. The graph shows the effects of placebo versus the two doses of Doxepin on polysonography minutes awake, or objective recordings of minutes a week. Again, at baseline, you could see there was no difference between the groups. At night one, already you can see separation between the two Doxepin groups and placebo favoring the effects of Doxepin. And by night 85, you can see that these effects were sustained for the entire duration of the study so that both doses of Doxepin, one and three milligrams, reduced wakefulness in this elderly's sample of subjects relative to placebo for the full 85 days of the trial. So Doxepin may be beneficial not just for helping people fall asleep but also for helping people stay asleep and these effects seem to be sustained at least for the 85 days of this particular trial.

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